An important issue facing the pharmaceutical and biotechnology industries is the limited availability of effective, non-toxic delivery systems for hydrophobic therapeutic compounds. For example, paclitaxel, the treatment of choice for tumors of the breast and ovary, is hydrophobic. Therefore, clinical administration of paclitaxel requires dispersion in an oil and ethanol excipient that has been linked to unwanted side effects.
Synthetic polymers have shown advantages as delivery vehicles for many pharmacological materials, providing increased solubility and stability of bound therapeutic compounds and the opportunity for targeted delivery to a restricted population of cells. Nanospheres, i.e., carriers with a size in the submicron range, are desirable for intravascular administration. For this purpose, the recent advances in supramolecular chemistry allow designing materials of superior characteristics.
For parenteral delivery systems, it has been shown that nano-sized particles and liposomes have great potential in cancer therapy due to their ability to extravasate from the leaky vasculature of tumors. To achieve this objective, various nano-sized particles or colloidal carriers such as nanospheres, polymeric micelles, liposomes, and surface modified nanoparticles have been proposed. However, the distribution of drugs and carriers in the body, undesirable side effects, rapid clearance by macrophage, thermal instability, structural fragility and low drug loading efficiency, among other factors, have limited these approaches and only a few such delivery systems have progressed toward clinical use.
For liposomal systems, their poor shelf stability and insufficient loading has been a substantial barrier. A number of polymeric systems have been investigated, with PLGA [poly(D,L-lactide-co-glycolide)] and PLA-PEG [poly(D,L-lactic acid)-poly(ethylene glycol)] being the most widely studied because they are biodegradable, of low antigenicity, and approved for drug use but their reported drug incorporation levels have been generally quite low, thus making it difficult to encapsulate sufficient drug for therapeutic efficacy. Improved drug incorporation has been seen using cyanoacrylate polymers, but these systems show some toxicity. Another disadvantage of many of the nanoparticles produced using the nanoprecipitation/solvent extraction technique is the need for a surfactant during nanoparticle formation. Sufficient removal of the surfactant and/or residual solvent is always a problem.
Of particular interest are nanoparticles formed via the self-assembly of block copolymers. Similar to low molecular weight lipid or surfactant molecules, amphiphilic block copolymers consist of at least two parts, a hydrophilic block and a hydrophobic block. Such amphiphilic block copolymers, driven by their hydrophobicity, can self-assemble in aqueous solution. At high concentrations, they may build lamellar liquid crystalline phases whereas, in dilute aqueous solution, they may form superstructures of various shapes like micelles or vesicular structures.
A suitable neutral amphiphilic block copolymer forms spontaneously nanometer-sized, well-defined hollow sphere structures in dilute aqueous solution. These structures can be viewed as the high molecular weight analogues of lipid or surfactant molecules. However due to their slow dynamic, they form much more stable superstructures than conventional liposomes. Furthermore, liposomes, e.g., spherically closed lipid bilayers, are rapidly recognized by the immune system and cleared from the blood stream. Due to the wide variety of block copolymer chemistry one can prepare an entirely synthetic material to avoid immunogenic reactions.
Although it is well known that suitable block copolymers can form nanospheres, few were designed to self-assemble into biocompatible and biodegradable structures in dilute aqueous solution. One example of spontaneous aggregation of an amphiphilic block oligomer has been reported with a poly(methyloxazoline)-block-poly(dimethyl-siloxane)-block-poly (methyl-oxazoline), PMOXA-PDMS-PMOXA triblock oligomer. Injection combined with extrusion techniques leads to the formation of vesicles whose size can be controlled between 50 and 500 nm. However, there remains a need for non-cytotoxic, biodegradable triblock copolymer vesicles.
Block copolymer vesicles are of interest for drug delivery applications for a number of reasons. First of all, hydrophobic drugs can be physically entrapped in the core of block copolymer micelles and transported at concentrations that can exceed their intrinsic water-solubility. Secondly, the hydrophilic blocks, which are often composed of poly(ethylene oxide) (PEO), can form hydrogen bonds with the aqueous surroundings and form a tight shell around the micellar core. As a result, the contents of the hydrophobic core are effectively protected against hydrolysis and enzymatic degradation. In addition, the PEO corona prevents recognition by the reticuloendothelial system and therefore preliminary elimination of the micelles from the bloodstream.
Consequently, the use of polymeric nanoparticles for the advantages of stability, cost, and ease of formulation is more preferable. It is expected, that drug incorporation and control of drug release, could be altered by the introduction of moieties into the polymers, which could increase the level of interaction with the drug. This strategy requires biodegradable polymers to enable in vivo biodegradation and subsequent removal from the body.